Scavenger resin and processes for the use thereof

ABSTRACT

Scavenger resins comprising pendant groups specific for the removal of primary amines form solution in the presence of secondary amines are provided. Processes for the use of these scavenger resins, especially in solid phase synthesis, for the removal of primary amines from solution or for the removal of electrophiles from solution are provided.

[0001] This invention relates to scavenger resins and to processes whichuse the scavenger resin for the selective removal of primary amines orfor the removal of electrophiles from solution.

[0002] Over the past few years, the exploration and utilization ofcombinatorial chemistry (and multi parallel synthesis) as apharmaceutical drug discovery technology has rapidly evolved. The fieldof combinatorial/multi parallel chemistry has expanded to include notonly solid and solution-phase methods for expedited compound synthesis,but also hybrid approaches which combine the purification advantages ofsolid-phase synthesis with the flexibility of solution-phase synthesis.(Kaldor, S. W. and Siegel, M. G., Curr. Opin. Chem. Biol. 1997, 1,101-106 and Thompson, L. A. and Ellman J. A., Chem. Rev. 1996, 96,555-600) Inherent in any approach to produce chemical libraries is theneed to rapidly purify, isolate, and manipulate chemical library membersduring their preparation.

[0003] Polymeric scavenging reagents have emerged as useful tools forcombinatorial synthesis, particularly, for solution-phase chemicallibrary synthesis. These materials are employed to remove, or scavenge,unwanted reagents or bi-products and thus aid in the purification ofmaterials. (Creswell, M. W. et. al., Tetrahedron, 1998, 54, 3983-3998;Kaldor, S. W. et. al., Tetrahedron Lett. 1996, 37, 7193-7196; Flynn, D.L. et. al., S., J. Am. Chem. Soc. 1997, 119, 4874-4882; Kaldor, S. W.et. al., Bioorg. Med. Chem. Lett. 1996, 24(6), 3041-3044; Caldarelli, M.et. al., J. Chem. Soc., Perkin Trans. 1. 1999, 107-110; Booth, R. J. andHodges, J. C., J. Am. Chem. Soc. 1997, 119, 4882-4886; Gayo, L. M. andSuto, M. J., Tetrahedron Lett. 1997, 38, 513-516; and Siegel, M. G. et.al., Tetrahedron Left. 1997, 38, 3357-3360). Typically, the polymericscavengers are added after the chemical reaction is complete to removeexcess reactants and bi-products. The resulting resin bound reactantsare removed by simple filtration leaving the product in solution.Examples of polymeric scavenger reagents include:

[0004] All the above resins are made by initial synthesis of apolystyrene or polystyrene copolymer bead followed by one or morechemical modification steps to introduce the scavenging functionality.For example, the isocyanate functional bead which is sold as a scavengerfor amines can be prepared from the Merrified resin via the amino methylpolystyrene:

[0005] The resins used are typically lightly crosslinked polystyrenes (1to 3% divinyl benzene) which typically require solvents that will swellthe resin to allow reagents to access the polymer bound functionalgroups. Alternatively the resin could be a macroporous resin (highdivinylbenzene content) which has permanent porosity allowing reactantsto access the functional groups independent of the solvent type.

[0006] One area of synthesis where the use of scavenger resins ispotentially useful is for example in the synthesis of secondary amines.Secondary amines are important pharmacophores in many biologicallyactive compounds. Often, they are prepared by reductive alkylation ofprimary amines with aldehydes or ketones. To alleviate problems of overalkylation, an excess of primary amine is employed. However, thispresents problems with purification in that the primary amine has to beselectively removed in the presence of the secondary amine.

[0007] Methyl isocyanate, isothiocyanate and N-methylisatoic anhydrideresins all react rapidly with both primary and secondary amines at roomtemperature. These resins are electrophilic scavengers and show poorselectivity for primary amines over secondary amines. Thebenzyloxybenzaldehye polystyrene resin is also an electrophilicscavenger and can be used to selectively sequester primary amines in thepresence of secondary amines. However, the benzaldehyde resins whichhave been reported are not particularly stable and may be oxidized inair. There is therefore a need for functionalised resins which act aselectrophilic scavengers and exhibit selectivity for primary amines andshow good chemical stability.

[0008] According to a first aspect of the present invention there isprovided a process for removing primary amines from solution wherein asolution comprising a primary amine is contacted with a scavenger resin,whereby the scavenger resin binds to at least some of the primary aminein solution thereby decreasing the amount of primary amine in solution,characterised in that the scavenger resin comprises pendant groupsselected from 1,3ketoesters or 1,3-ketoamides or mixtures thereofattached to a polymer support.

[0009] In the process of the present invention, the scavenger resin maybe added to a solution comprising a primary amine. The resin is thenseparated from the solution, preferably by filtration, the contact timebeing such as to allow for at least partial depletion of primary aminein solution. Alternatively, a solution comprising a primary amine ispassed through a mass or column of resin, the dwell time being such asto allow for at least partial depletion of primary amine in solution.Contact or dwell time can be determined by monitoring reductions inlevels of primary amine in solution.

[0010] The process of the present invention may be carried out attemperatures ranging from −100 to 250° C., preferably from −10 to 100°C., more preferably from 10 to 40° C. and most preferably at ambienttemperature, for example from 15 to 30° C.

[0011] In the process of the present invention preferably sufficientscavenger resin is employed to effect the removal of substantially allthe primary amine. Preferably, the ratio of scavenger resin to primaryamine solution employed is directly related to the concentration ofprimary amine present and the percentage of 1,3-ketoester and/or1,3ketoamide active functionality on the scavenger resin. The ratio ofmolar concentration of 1,3-ketoester and/or 1,3-ketoamide activefunctionality on the scavenger resin to molar concentration of amine insolution may be in the range from 1:1 to 100:1. Preferably an excess of1,3-ketoester and/or 1,3-ketoamide active functionality is employed, forexample ratios in the range of 1:1 to 20:1 or more preferably in therange of 1:1 to 4:1. Such excesses may promote effective and fastremoval of the primary amine.

[0012] The scavenger resins employed in the process of the presentinvention can have 1,3-ketoester or 1,3-ketoamide pendant groupsattached directly to a polymer support or attached to a polymer supportthrough a linking group. Preferably, the 1,3-ketoester or 1,3-ketoamidependant groups are attached to a polymer support through a linkinggroup. Suitable linking groups include those groups as set out below inthe definition of L.

[0013] The scavenger resins are preferably organic resins, particularlysynthetic organic resins.

[0014] The 1,3-ketoester or 1,3-ketoamide pendant groups include groupsof formula 1:

[0015] wherein R¹ is an optionally substituted hydrocarbyl,perhalogenated hydrocarbyl or heterocyclyl group;

[0016] X is O or NR², wherein the free valence of O or NR² is bonded toa polymer support optionally via a linker; and

[0017] R² is hydrogen, an optionally substituted hydrocarbyl, orheterocyclyl group.

[0018] Hydrocarbyl groups which may be represented by R¹ and R² includealkyl, alkenyl and aryl groups, and any combination thereof, such asaralkyl and alkaryl, for example benzyl groups.

[0019] Alkyl groups which may be represented by R¹ and R² include linearand branched alkyl groups comprising up to 20 carbon atoms, particularlyfrom 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. Whenthe alkyl groups are branched, the groups often comprise up to 10branched chain carbon atoms, preferably up to 4 branched chain atoms. Incertain embodiments, the alkyl group may be cyclic, commonly comprisingfrom 3 to 10 carbon atoms in the largest ring and optionally featuringone or more bridging rings. Examples of alkyl groups which may berepresented by R¹ and R² include methyl, ethyl, propyl, 2-propyl, butyl,2-butyl, t-butyl and cyclohexyl groups.

[0020] Alkenyl groups which may be represented by R¹and R² includeC₂₋₂₀, and preferably C₂₋₆ alkenyl groups. One or more carbon-carbondouble bonds may be present. The alkenyl group may carry one or moresubstituents, particularly phenyl substituents. Examples of alkenylgroups include vinyl, styryl and indenyl groups.

[0021] Aryl groups which may be represented by R¹ and R² may contain 1ring or 2 or more fused rings which may include cycloalkyl, aryl orheterocyclic rings. Examples of aryl groups which may be represented byR¹ and R² include phenyl, tolyl, fluorophenyl, chlorophenyl,bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenylgroups.

[0022] Perhalogenated hydrocarbyl groups which may be represented by Rindependently include perhalogenated alkyl and aryl groups, and anycombination thereof, such as aralkyl and alkaryl groups. Examples ofperhalogenated alkyl groups which may be represented by R include —CF₃and —C₂F₅.

[0023] Heterocyclic groups which may be represented by R¹ andR²independently include aromatic, saturated and partially unsaturatedring systems and may constitute 1 ring or 2 or more fused rings whichmay include cycloalkyl, aryl or heterocyclic rings. The heterocyclicgroup will contain at least one heterocyclic ring, the largest of whichwill commonly comprise from 3 to 7 ring atoms in which at least one atomis carbon and at least one atom is any of N, O, S or P. Examples ofheterocyclic groups which may be represented by R¹ and R² includepyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl,isoquinolyl, imidazoyl and triazoyl groups.

[0024] When any of R¹ or R² is a substituted hydrocarbyl or heterocyclicgroup, the substituent(s) should be such so as not to adversely affectthe rate or selectivity of the reaction. Optional substituents includehalogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl,perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono ordi-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides,sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are asdefined for R¹ and R² above. One or more substituents may be present.

[0025] R¹ is preferably an alkyl group, most preferably a methyl group.

[0026] R² is preferably hydrogen or an alkyl group. When R² is an alkylgroup, preferably R² is a methyl group. Most preferably R² is hydrogen.

[0027] The polymer support may be derived from the polymerisation of acomposition comprising one or more monomers, and is preferably derivedfrom the polymerisation a composition comprising of two or moremonomers. The monomers may contain one or more polymerisable doublebonds. Preferably the polymer support is derived from the polymerisationof a composition comprising one or more monomers containing only onepolymerisable double bond, and one or more monomers containing two ormore polymerisable double bonds. Most preferably the polymer support isderived from the polymerisation of a composition comprising one or twomonomers containing only one polymerisable double bond, and one monomercontaining two or three polymerisable double bonds.

[0028] Examples of monomers containing only one polymerisable doublebond include styrene and substituted styrenes such as α-methyl styrene,methyl styrene, t-butyl styrene, bromo styrene and acetoxy styrene;alkyl esters of mono-olefinically unsaturated dicarboxylic acids such asdi-n-butyl maleate and di-n-butyl fumarate; vinyl esters of carboxylicacids such as vinyl acetate, vinyl propionate, vinyl laurate and vinylesters of versatic acid such as VeoVa 9 and VeoVa 10 (VeoVa is atrademark of Shell); acrylamides such as methyl acrylamide and ethylacrylamide; methacrylamides such as methyl methacrylamide and ethylmethacrylamide; nitrile monomers such as acrylonitrile andmethacrylonitrile; and esters of acrylic and methacrylic acid,preferably optionally substituted C₁₋₂₀alkyl and C₁₋₂₀cycloalky estersof acrylic and methacrylic acid, such as methyl acrylate, ethylacrylate, n-butyl acrylate, 2-ethylhexyl acrylate, i-propyl acrylate,and n-propyl acrylate, methyl methacrylate, ethyl methacrylate, n-butylmethacrylate, 2-ethylhexyl methacrylate, i-propyl methacrylate, n-propylacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate,N,N-dimethylaminoethyl acrylate and N,N-dimethylaminoethyl methacrylate.Functional derivatives of the foregoing monomers containing only onepolymerisable double bond can also be employed.

[0029] Examples of monomers containing two or more polymerisable doublebonds include divinylbenzene (DVB), trivinylbenzene, and multifunctionalacrylates and methacrylates such as ethylene glycol diacrylate, ethyleneglycol dimethacrylate, trimethylolpropane triacrylate,trimethylolpropane trimethacrylate, ethylene bisacrylamide,pentaerythritol triacrylate, pentaerythritol tetraacrylate,pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate andN,N-bis-acryloyl ethylene diamine.

[0030] In certain embodiments, polymer supports are derived from thepolymerisation of monomers selected from styrene and substitutedstyrenes, divinylbenzene, esters of acrylic, esters of methacrylic acid,alkyl esters of mono-olefinically unsaturated dicarboxylic acids, vinylesters of carboxylic acids, acrylamides, methacrylamides and functionalderivatives thereof. Preferred polymer supports are derived form thepolymerisation of monomers selected from styrene and substitutedstyrenes, divinylbenzene, esters of acrylic acid and esters ofmethacrylic acid. Particularly preferred polymer supports are derivedfrom the polymerisation of a mixture of styrene monomers, divinylbenzenemonomers and methacrylate ester monomers, or are derived from thepolymerisation of a mixture of styrene monomers, divinylbenzene monomersand acrylate ester monomers.

[0031] When polymer supports are derived from the polymerisation ofcompositions comprising monomers containing two or more polymerisabledouble bonds, the polymer support can exhibit varying degrees ofcrosslinking. The extent of crosslinking in these polymers can beexpressed in percentage terms and corresponds to the number of moles ofpolymerisable double bonds derived from monomers containing two or morepolymerisable double bonds as a percentage of the total number of molesof polymerisable double bonds.

[0032] Where the polymer support of the scavenger resin exhibits onlylow levels of crosslinking, such as from 1% to 5%, or commonly from 1%to 3%, these crosslinked scavenger resins are routinely contacted withsolvents which cause the scavenger resin to swell. Such scavenger resinsare frequently referred to as microporous resins.

[0033] In many embodiments, the microporous resin is swelled in thesolvent of choice to allow ready access to the functional groups on theresin. Solvents of choice can be predicted by considering the polymercomposition and are often those solvents which would be “good solvents”for a theoretical linear polymer which may be made from a similarcomposition but with no crosslinking agent present.

[0034] Preferred swell ratios for a microporous resin fall in the rangeof from 5 to 20. The swell ratio is defined as:${{Swell}\quad {Ratio}} = \frac{{Vol}_{final} - {Vol}_{initial}}{{Vol}_{initial}}$

[0035] Vol_(final)=Final volume occupied by resin after allowing theresin to fully swell in a given solvent.

[0036] Vol_(initial)=Initial dry bed volume of resin.

[0037] Where the polymer support of the scavenger resin exhibits higherlevels of crosslinking, such as from 20% to 90%, or commonly from 30% to80%, these highly crosslinked scavenger resins often have permanentporosity thus access of reagents to the pendant groups attached to thepolymer support is mainly independent of solvents. Such scavenger resinsare frequently referred to as macroporous resins.

[0038] The term macroporous indicates a class of resins which have apermanent well developed porous structure. Importantly, these resins canhave much higher surface areas (as measured by nitrogen BET) in the drystate than gel type resins. Typically, surface areas in the dry statecan range from 50 to 1000 m²/g. Although there is no universallyaccepted definition of a macroporous resin, in the case of styrene-DVBresins it has been suggested that a macroporous resin may be defined asresin which in the dry state when exposured to cyclohexane exhibits acyclohexane uptake of at least 0.1 m²g⁻¹ over 16 h (Millar, J. R. et.al., J. Chem. Soc., 1996, 218.).

[0039] Macroporous resins are often formed when the compositioncomprising monomers containing two or more polymerisable double bonds ispolymerised in the presence of a porogen. The porogen causes phaseseparation of the polymer matrix. Removal of the porogen and dryingyields rigid, opaque, permanently porous beads. Phase separation iscontrolled by the nature and level of the porogen employed, and thelevel of crosslinking agent employed.

[0040] The selection of monomers and/or crosslinking agents from whichthe scavenger resin is derived may in part be dictated by the desiredmorphology of the scavenger resin, and the solvent or reaction systemsin which the scavenger resins will be employed. The relationshipsbetween morphology and monomer compositions are reviewed in Sherrington,D. C., J. Chem. Soc., Chem Commun., 1998, 2275, of which the teaching ofpages 2278 to 2284 are incorporated herein by reference.

[0041] Where the pendant 1,3-ketoester or 1,3-ketoamide groups areattached either directly or by means of a linker to the polymer support,the attachment is made to the repeat units of the polymer support. Wherethe polymer support is derived from more than one monomer type, therewill be more than one type of repeat unit. Preferably the 1,3-ketoesteror 1,3-ketoamide groups are attached either directly or by means of alinker to only one type of repeat unit. Preferably the repeat unit towhich the 1,3-ketoester or 1,3-ketoamide groups are attached eitherdirectly or by means of a linker is derived from a single monomer typewhich is a methacrylate or acrylate derived monomer.

[0042] Preferably, where the pendant 1,3-ketoester or 1,3-ketoamidegroup are attached by means of a linker to the polymer support, thescavenger resin is derived from the polymerisation of a compositioncomprising a functionalised monomer comprising pendant 1,3-ketoester or1,3-ketoamide groups attached by means of a linker to a single monomertype. More preferably, the scavenger resin is derived from thepolymerisation of a composition comprising two or more monomers, whereinat least one monomer is a functionalised monomer comprising pendant1,3-ketoester or 1,3-ketoamide groups attached by means of a linker to asingle monomer type. Most preferably the scavenger resin is derived fromthe polymerisation of a composition comprising one or more monomerscontaining only one polymerisable double bond, one or more monomerscontaining two or more polymerisable double bonds, and a functionalisedmonomer comprising pendant 1,3-ketoester or 1,3-ketoamide groupsattached by means of a linker to a single monomer type. Polymer supportsderived from the polymerisation of a composition comprising one or twomonomers containing only one polymerisable double bond, one monomercontaining two or three polymerisable double bonds and a functionalisedmonomer comprising pendant 1,3-ketoester or 1,3-ketoamide groupsattached by means of a linker to a single monomer type are highlypreferred.

[0043] Scavenger resins may be derived from the polymerisation ofcompositions comprising a functionalised monomer comprising pendant1,3-ketoester or 1,3-ketoamide groups attached by means of a linker to asingle monomer type, and one or more monomers selected from the groupcomprising styrene and substituted styrenes, such as α-methyl styrene,methyl styrene, t-butyl styrene, bromo styrene and acetoxy styrene;alkyl esters of mono-olefinically unsaturated dicarboxylic acids, suchas di-n-butyl maleate and di-n-butyl fumarate; vinyl esters ofcarboxylic acids such as vinyl acetate, vinyl propionate, vinyl laurateand vinyl esters of versatic acid such as VeoVa 9 and VeoVa 10 (VeoVa isa trademark of Shell); acrylamides such as methyl acrylamide and ethylacrylamide; methacrylamides such as methyl methacrylamide and ethylmethacrylamide; nitrile monomers such as acrylonitrile andmethacrylonitrile; esters of acrylic and methacrylic acid, preferablyoptionally substituted C₁₋₂₀alkyl and C₁₋₂₀cycloalky esters of acrylicand methacrylic acid, such as methyl acrylate, ethyl acrylate, n-butylacrylate, 2ethylhexyl acrylate, i-propyl acrylate, and n-propylacrylate, methyl methacrylate, ethyl methacrylate, n-butyl methacrylate,2-ethylhexyl methacrylate, i-propyl methacrylate, n-propyl acrylate,hydroxyethyl acrylate, hydroxyethyl methacrylate, N,N-dimethylaminoethylacrylate and N,N-dimethylaminoethyl methacrylate; divinylbenzene;trivinylbenzene; and multifunctional acrylates and methacrylates such asethylene glycol diacrylate, ethylene glycol dimethacrylate,trimethylolpropane triacrylate, trimethylolpropane trimethacrylate,ethylene bisacrylamide, pentaerythritol triacrylate, pentaerythritoltetraacrylate, pentaerythritol trimethacrylate, pentaerythritoltetramethacrylate and N,N-bis-acryloyl ethylene diamine. The singlemonomer type to which the pendant 1,3-ketoester or 1,3-ketoamide groupsare attached by means of a linker is preferably a methacrylate oracrylate derived monomer unit.

[0044] Preferably the functionalised monomer comprising pendant1,3-ketoester or 1,3ketoamide groups has the general formula 2:

[0045] wherein

[0046] X, R¹ and R² are as defined herein before above;

[0047] R³ is an optionally substituted hydrocarbyl, perhalogenatedhydrocarbyl or heterocyclyl group; and

[0048] L is a linking group.

[0049] Optionally substituted hydrocarbyl, perhalogenated hydrocarbyl orheterocyclyl groups which may be represented by R³ are as defined for R¹above.

[0050] Linking groups which may be represented by L include optionallysubstituted methylene, polymethylene, ether, polyether or cyclicbridging units.

[0051] Methylene and polymethylene bridging units which may berepresented by L include linear and branched alkylene chains comprisingup to 20 carbon atoms, particularly from 1 to 7 carbon atoms andpreferably from 1 to 5 carbon atoms. When the alkyl groups are branched,the groups often comprise up to 10 branched chain carbon atoms,preferably up to 4 branched chain atoms. Examples of alkylene chainswhich may be represented by L include —CH₂—, —CH₂CH₂—, —(CH₂)₃—,—CH₂CH(CH₃)—, and —CH₂C(CH₃)₂—chains.

[0052] Ether and polyether bridging units which may be represented by Linclude linear and branched alkylene-oxy-alkylene chains orpoly(alkyleneoxy)-alkylene chains comprising up to 150 carbon atoms andup to 40 oxygen atoms, particularly from 2 to 15 carbon atoms and from 1to 4 oxygen atoms, and preferably from 2 to 6 carbon atoms and from 1 to2 oxygen atoms. Examples of alkylene-oxy-alkylene chains orpoly(alkyleneoxy)-alkylene chains which may be represented by L include—CH₂—O—CH₂—, —CH₂CH₂—O—CH₂CH₂—, —(CH₂)₃—O—(CH₂)₃—,—CH₂CH(CH₃)—O—CH₂CH₂—, —CH₂CH(CH₃)—O—CH₂CH(CH₃)— chains, and also—[CH₂CH₂—O)]_(n)—CH₂CH₂— and —[CH₂CH(CH₃)—O]_(n)—CH₂CH(CH₃)— chainswhere n=2, 3 or 4.

[0053] Cyclic bridging units which may be represented by L includearomatic, saturated and partially unsaturated ring systems and mayconstitute 1 ring or 2 or more fused rings which may include cycloalkyl,aryl or heterocyclic rings. In certain embodiments, cycloalkyl and arylrings commonly comprise from 3 to 10 carbon atoms in the largest ring,and heterocyclic rings commonly comprise from 3 to 7 ring atoms in whichat least one atom is carbon and at least one atom is any of N, O, S orP. Examples of aromatic, saturated and partially unsaturated ringsystems which may be represented by L include —CH₂C₆H₄CH₂— and—CH₂C₆H₁₀CH₂—.

[0054] Examples of functionalised monomers comprising pendant1,3-ketoester or 1,3ketoamide groups include:

[0055] In certain highly preferred embodiments the functionalisedmonomer comprising pendant 1,3-ketoester or 1,3-ketoamide groupsattached by means of a linker to a single monomer type isacetoacetoxyethyl methacrylate having the formula:

[0056] In a preferred embodiment, scavenger resins are derived from thepolymerisation of compositions comprising a functionalised monomercomprising pendant 1,3-ketoester or 1,3-ketoamide groups selected fromthe group consisting of monomers having the formulae:

[0057] and one or more monomers selected from the group consisting ofstyrene and substituted styrenes, such as α-methyl styrene, methylstyrene, t-butyl styrene, bromo styrene and acetoxy styrene; alkylesters of mono-olefinically unsaturated dicarboxylic acids, such asdi-n-butyl maleate and di-n-butyl fumarate; vinyl esters of carboxylicacids such as vinyl acetate, vinyl propionate, vinyl laurate and vinylesters of versatic acid such as VeoVa 9 and VeoVa 10 (VeoVa is atrademark of Shell); acrylamides such as methyl acrylamide and ethylacrylamide; methacrylamides such as methyl methacrylamide and ethylmethacrylamide; nitrile monomers such as acrylonitrile andmethacrylonitrile; esters of acrylic and methacrylic acid, preferablyoptionally substituted C₁₋₂₀alkyl and C₁₋₂₀cycloalky esters of acrylicand methacrylic acid, such as methyl acrylate, ethyl acrylate, n-butylacrylate, 2-ethylhexyl acrylate, i-propyl acrylate, and n-propylacrylate, methyl methacrylate, ethyl methacrylate, n-butyl methacrylate,2-ethylhexyl methacrylate, i-propyl methacrylate, n-propyl acrylate,hydroxyethyl acrylate, hydroxyethyl methacrylate, N,N-dimethylaminoethylacrylate and N,N-dimethylaminoethyl methacrylate; divinylbenzene;trivinylbenzene; and multifunctional acrylates and methacrylates such asethylene glycol diacrylate, ethylene glycol dimethacrylate,trimethylolpropane triacrylate, trimethylolpropane trimethacrylate,ethylene bisacrylamide, pentaerythritol triacrylate, pentaerythritoltetraacrylate, pentaerythritol trimethacrylate, pentaerythritoltetramethacrylate and N,N-bis-acryloyl ethylene diamine.

[0058] In a more preferred embodiment, scavenger resins are derived fromthe polymerisation of compositions comprising one or more monomersselected from the group consisting of acetoacetoxyethyl acrylate,acetoacetoxyethyl methacrylate, acetoacetoxypropyl acrylate, andacetoacetoxypropyl methacrylate, one or more monomers selected from thegroup consisting of styrene, methyl acrylate, ethyl acrylate, methylmethacrylate, ethyl acrylate, and one or more monomers selected from thegroup consisting of divinylbenzene, trivinylbenzene ethylene glycoldiacrylate, ethylene glycol dimethacrylate, trimethylolpropanetriacrylate, trimethylolpropane trimethacrylate, ethylene bisacrylamide,pentaerythritol triacrylate, pentaerythritol tetraacrylate,pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate andN,N-bis-acryloyl ethylene diamine.

[0059] In a highly preferred embodiment, scavenger resins are derivedfrom the polymerisation of compositions comprising acetoacetoxyethylmethacrylate, styrene and divinylbenzene.

[0060] Where the scavenger resin is derived from the polymerisation of acomposition comprising one or two monomers containing only onepolymerisable double bonds, one monomer containing two or threepolymerisable double bonds, and a functionalised monomer of generalformula (2), the mole ratio of the total number of moles of monomerscontaining only one polymerisable double bonds:functionalised monomer ofgeneral formula (2) may be from 100:1 to 1:100, is preferably from 70:30to 1:99 and most preferably is from 60:40 to 15:85. The level ofcrosslinking, as defined herein above, may be from 0.5% to 80%,preferably from 1% to 60% and most preferably from 1% to 40%.

[0061] When the scavenger resin is derived from the polymerisation ofstyrene, divinylbenzene and a functionalised monomer of general formula(2), the mole ratio of styrene: functionalised monomer of generalformula (2) is often from 100:1 to 1:100, is preferably from 70:30 to1:99 and most preferably is from 60:40 to 15:85. The level ofcrosslinking is often from 0.5% to 80%, preferably from 1% to 60% andmost preferably from 1% to 40%.

[0062] Scavenger resins prepared from functionalised monomers comprisingpendant 1,3-ketoester or 1,3-ketoamide groups are preferably produced asbeads. The beads often range in size from diameters of 10 μm to 2000 μm,preferably from 50 μm to 1000 μm, and most preferably from 75 μm to 500μm.

[0063] The scavenger resins may be prepared by an aqueous suspensionpolymerisation process, for example as described in Journal of AppliedPolymer Science, 1982, 27, 133-138. The monomers can be suspended asdroplets often of diameter from 1 μm to 1000 μm in water. Preferablystabilisers are added to prevent agglomeration of the droplets. Examplesof stabilisers which may be added include polyvinyl alcohol, polyacrylicacid, polyvinyl pyrrolidone, polyalkylene oxide, barium sulphate,magnesium sulphate and sodium sulphate. Agitation of the suspension ispreferably employed. The method of agitation employed may help to assistin maintaining the suspension. A free radical initiator commonly servesto initiate polymerisation. The free radical initiator employed isselected according to the types of monomers present. Examples of freeradical initiators which may be used to prepare scavenger resins whichmay be employed in processes of the present invention include benzoylperoxide, dioctanoyl peroxide, 2,2′-azobisisobutyronitrile and2,2′-azobis(2,4-dimethylvaleronitrile). The selection of a suitabletemperature range may be influenced by the nature of the monomers andthe initiator present. Polymerisation of the monomers is commonlycarried out at temperatures ranging from 15 to 160° C., preferably from50 to 90° C. The resultant scavenger resin may be isolated byfiltration, optionally washed with one or more solvents. Suitablesolvents for washing the scavenger resin include tetrahydrofuran,methanol and water. The resultant scavenger resin may be dried and thebeads classified according to size by for example sieving.

[0064] The process of the present invention may be carried out in thepresence of a solvent. Suitable solvents include any solvent capable ofswelling the crosslinked resin or for macroporous resins, any solventcapable of entering the pores. Suitable solvents may be selected frompolar, non-polar, protic and aprotic solvents. Examples of suitablesolvents include CH₂Cl₂, toluene, THF, methanol, dimethylformamide,propan-2-ol, and mixtures thereof. Propan-2-ol is a preferred solvent.

[0065] In the process of the present invention, the scavenger resin can,through reaction of the carbonyl groups present, act as an electrophilicreagent removing nucleophiles, particularly primary amines, fromsolution. However, the scavenger resin may act as a nucleophilic reagentremoving electrophiles from solution by, for example, reaction of theelectrophile with the active methylene functionality.

[0066] According to a second aspect of the present invention there isprovided a process for removing of electrophiles from solution wherein asolution comprising an electrophile is contacted with a scavenger resin,whereby the scavenger resin binds to at least a some of the electrophilein solution thereby decreasing levels of electrophile in solutioncharacterised in that the scavenger resin comprises pendant groupsselected from 1,3ketoesters or 1,3-ketoamides or mixtures thereofattached to a polymer support.

[0067] Scavenger resins which may be employed in the second aspect ofthe present invention include the scavenger resins as hereinbeforedescribed in the first aspect of the present invention.

[0068] In the process of the present invention, the scavenger resin maybe added to a solution comprising an electrophile. The resin is thenseparated from the solution, preferably by filtration, the contact timebeing such as to allow for at least partial depletion of electrophile insolution. Alternatively, a solution comprising an electrophile is passedthrough a mass or column of resin, the dwell time being such as to allowfor at least partial depletion of electrophile in solution. Contact ordwell time can be determined by monitoring reductions in levels ofelectrophile in solution.

[0069] The process of the present invention may be carried out attemperatures ranging from −100 to 250° C., preferably from −10 to 100°C., more preferably from 10 to 40° C. and most preferably at ambienttemperature, for example from 15 to 30° C.

[0070] In the process of the present invention, sufficient scavengerresin is employed to effect the removal of substantially all theelectrophile. The ratio of scavenger resin to electrophile solutionemployed will be in direct relation to the concentration of electrophilepresent and percentage 1,3-ketoester or 1,3-ketoamide activefunctionality. The ratio of molar concentration of 1,3-ketoester or1,3-ketoamide active functionality on the scavenger resin to molarconcentration of electrophile in solution may be in the range from 1:1to 100:1. Preferably an excess of 1,3-ketoester and/or 1,3-ketoamideactive functionality is employed, for example ratios in the range of 1:1to 20:1 or more preferably in the range of 1:1 to 4:1. Such excesses maypromote effective and fast removal of the electrohpile.

[0071] Electrophiles which may effectively be removed by the process ofthe present invention, include those electrophiles which undergoreaction with active methylene compounds to form covalently bondedspecies linking the electrophile to the active methylene compound.Examples of electrophiles include formaldehyde, aldehydes, isocyanates,diazonium salts.

[0072] The process of the present invention may be carried out in thepresence of a solvent. Suitable solvents include any solvent capable ofswelling the crosslinked resin or for macroporous resins, any solventcapable of entering the pores. Suitable solvents may be selected frompolar, non-polar, protic and aprotic solvents, especially aproticsolvents. Examples of suitable solvents include CH₂Cl₂, toluene, THF,dimethylformamide, and mixtures thereof. Trimethyl orthoformate is apreferred solvent

[0073] The scavenger resins of the present invention may find furtherapplication in solid phase synthesis whereby nucleophiles orelectrophiles which react with the scavenger resins may optionally besubjected to further reactions while attached to the scavenger resin.The nucleophile, electrophile or further derivative product may beisolated by cleavage of the product from the scavenger resin bychemical, enzymatic or other means.

[0074] The present invention also provides scavenger resins as definedin claims 3 to 9 and as defined in the first and second aspects of thepresent invention. Preferences for the scavenger resins are as definedfor the scavenger resins employed in the first and second aspects of thepresent invention. Especially preferred scavengers resins are thosescavenger resins employed in the first and second aspects of the presentinvention which are obtainable by aqueous suspension polymerisation,more preferably obtainable by the aqueous suspension polymerisationprocesses described with respect to the first aspect of the presentinvention. Many preferred scavenger resins comprise pendant groups whichare reactive with both electrophiles and nucleophiles. Scavenger resinsof the present invention are preferably in the form of beads as hereinbefore defined.

[0075] The invention is further illustrated, but not limited, by thefollowing examples.

EXAMPLES Example 1 Scavenger Resin Based on AcetoacetoxyethylMethacrylate/Styrene/Divinylbenzene

[0076] Distilled water (5.5 litres), sodium sulphate (5.35 g) and anaqueous solution of AIRVOL 540 (200 g of 2.5% w/w polyvinyl alcohol,AIRVOL is a trade name of Air Products Ltd) were heated to 65° C. in acylindrical 10 litre glass reactor and stirred with a stainless steelpaddle shaped stirrer blade at 160 rpm. Acetoacetoxyethyl methacrylate(615.5g) was added to a mixture of styrene (805.3 g), technical gradedivinyl benzene (17.2 g), and Wako V-65 (14.4 g) (2,2′-Azobis(2,4-dimethylvaleronitrile), supplied by Wako Chemicals GmbH). Thismonomer mixture was poured into the reactor vessel and the whole mixturestirred at 160 rpm at 65° C. for 6 hours. The mixture was then pouredinto a 50 mm mesh ‘top hat’ filter and washed with tap water for 30minutes. The wet beads were transferred to a beaker and allowed to standfor 16 hours in a 1:1 mixture of THF and distilled water (10 litres)before filtering through a sintered filter (porosity 2). The beads werewashed three times with THF (6 litres), once with THF/methanol (2:1, 2.5litres), once with THF/methanol (1:2, 2.5 litres, and three times withmethanol (1.5 litres) before drying in a vacuum oven to constant weight.

[0077] The beads were classified by sieving, as shown: Sieve meshsize >500 mm 134 g 17.56% 300-500 mm 350.3 g 45.92% 150-300 mm 273.3 g35.82% >150 mm 5.3 g  0.69%

[0078] The fraction in the range 150-300 mm was used subsequently. Ithad a swell ratio of 8.0 ml/g in THF. The FT-IR spectrum showed a strongband at 1722 cm−1 for the carbonyl group.

Example 2 Scavenger Resin Based on AcetoacetoxyethylMethacrylate/Styrene/Divinylbenzene

[0079] Distilled water (5.5 litres), sodium sulphate (5.35 g) and anaqueous solution of AIRVOL 540 (200 g of 2.5% w/w polyvinyl alcohol,AIRVOL is a trade name belonging to Air Products Ltd) (200 g) wereheated to 65° C. in a cylindrical 10 litre glass reactor and stirredwith a stainless steel paddle shaped stirrer blade at 160 rpm.Acetoacetoxyethyl methacrylate (932.5 g) was added to a mixture ofstyrene (486.4 g), technical grade divinyl benzene (19.0 g), and WakoV-65 (14.4 g) (2,2′-Azobis (2,4-dimethylvaleronitrile), supplied by WakoChemicals GmbH). This monomer mixture was poured into the reactor vesseland the whole mixture stirred at 165 rpm at 65° C. for 6 hours. Themixture was then poured into a 50 mm mesh ‘top hat’ filter and washedwith tap water for 30 minutes. The wet beads were transferred to abeaker and allowed to stand for 16 hours in a 1:1 mixture of THF anddistilled water (10 litres) before filtering through a sintered filter(porosity 2). The beads were washed three times with THF (6 litres),once with THF/methanol (2:1, 2.5 litres), once with THF/methanol (1:2,2.5 litres, and three times with methanol (1.5 litres) before drying ina vacuum oven to constant weight.

[0080] The beads were classified by sieving, as shown: Sieve meshsize >500 mm 23.7 g  1.95% 300-500 mm 193.1 g 15.87% 150-300 mm 899.8 g73.97% <150 mm 99.8 g  8.21%

[0081] The fraction in the range 150-300 mm was used subsequently. Ithad a swell ratio of 6.5 ml/g in THF. The FT-IR spectrum showed a strongband at 1722 cm−1 for the carbonyl group.

Example 3 Macroporous Scavenger Resins, Effects of Varying Diluent andCrosslinker

[0082] To a 1.5 l stirred flange flask, fitted with condenser and purgedwith nitrogen, was added an aqueous phase comprising distilled water(1130 ml), sodium sulphate (0.77 g), and an aqueous solution of AIRVOL540 (29 ml of 2.5% w/w polyvinyl alcohol). A monomer phase comprisingacetoacetoxyethyl methacrylate (118.9 g), divinylbenzene (80.5 g of 80%purity), diluent (100.0 g, see Table 1), and Wako V65 (1.9 g)(2,2′-Azobis (2,4-dimethylvaleronitrile) was made up in a 1 l conicalflask. The monomer phase was transferred to the flange flask at 65° C.whilst stirring at 420 r.p.m. The reaction mixture was stirred for fivehours then allowed to cool. The beads were recovered by filtrationfollowed by sequential washing with water (4×1 l), THF (3×500 ml),THF/MeOH (400 ml:200 ml), THF/MeOH (200 ml:400 ml) and MeOH (2×400 ml).The beads were then dried in the vacuum oven at 65° C.

[0083] A sample of the beads were analysed by Nitrogen BET using aMicrometrics Tristar 3000 to determine surface area and were analysed bymercury intrusion using a Micrometrics Autopore 9220 to determine poresize distribution. TABLE 1 summarises the effect of different diluentson the surface area and pore dimensions: Average Pore Total % Pore SizeSurface Dia- Pore Distribution DVB Area meter Volume 30- 300- Diluent %(m²/g) (Å) (cm³/g) 300 Å 1000 Å 1000 Å heptane 40 2.05 191.50 0.0098 1.133.8 65.1 heptane 20 2.72 220.96 0.0150 8.5 14.7 76.8 decanol 40 71.80218.94 0.3930 18.1 21.0 60.9

Example 4 Comparison of Reactivity of Scavenger Resin with Primary andSecondary Amines Under Varying Temperature and Solvent Conditions

[0084] To a solution of benzylamine (1.5 mmol) and a secondary amine(2.6 mmol of either N-benzylmethylamine or dibenzylamine) in solvent wasadded a portion of the scavenger resin prepared according to Example 2(see Table 2). An aliquot of the solution (10 μl) was taken from thesuspension at time intervals and diluted with acetonitrile (to 1 ml).The sample was analyzed by HPLC to determine the extent of removal ofthe benzylamine as a function of time. HPLC conditions: Gradient fromwater (0.1% TFA) to MeCN (0.042% TFA) over 20 minutes; I=254 nm.Benzylamine (t_(R) 6.9 min.); N-Benzylmethylamine (t_(R) 7.2 min.);dibenzylamine (t_(R) 9.7 min.)

[0085] Two pairs of amines were studied: benzylamine(BnNH2)/N-benzylmethylamine (BnNHMe) and benzylamine/dibenzylamine. Thetwo pairs of amines were reacted with the scavenger resin in twodifferent solvents, 2-propanol (2-PrOH) or tetrahydrofuran (THF), and atdifferent temperatures. The results are shown in Table 3, 4 and 5. Theprimary amine, benzylamine, was removed from solution whereas thesecondary amines, N-benzylmethylamine or dibenzylamine remainedprimarily in solution under the same conditions. The rate of removal ofprimary amine at room temperature was much slower than at 40° C. Thereaction of primary amine with scavenger resin was influenced bysolvent. In general, more primary amine was removed from solution when2-propanol was employed as solvent than when tetrahydrofuran isemployed. The results show that scavenger resin has high selectivity forthe primary amine, benzylamine. TABLE 2 Experimental Conditions employedin Experiments to show the removal of benzylamine in the presence ofsecondary amines with Scavenger Resin Expt. A B C D E F G H Solvents2-PrOH 2-PrOH THF MeOH/DCM MeOH MeOH/DCM 2-PrOH MeOH (ml) (8.0) (8.0)(8.0) (1:1 v/v) (4.0) (1:1 v/v) (4.0) (4.0) (4.0) (4.0) Temp (° C.) 4020 20 20 20 20 20 20 Molar  2  2  2  2  4  4  4  2 ratio (BnNH₂/ resin)

[0086] TABLE 3 Results of removal of benzylamine in the presence ofdibenzylamine Time Ratio (BnNH₂/Bn₂NH, %) Content of BnNH₂ (%) Contentof Bn₂NH (%) (hour) A B C A B C A B C 0 22.24 17.2 20.81 100 100 100 100100 100 1 7.79 14.0 16.8 28.77 69.13 87.66 82.12 84.65 100 2 5.88 12.5513.63 21.62 66 69.58 81.8 87.34 100 4 2.55 10.7 11.62 9.37 54.9 61.8681.77 86.32 100 6 1.6 7.83 8.96 5.82 39.14 45.78 80.78 81.12 100 7 1.416.86 6.41 5.23 34.2 33.77 82.54 85.55 100 9 1.05 3.09 4.77 3.91 14.7824.93 83.16 82.05 100

[0087] TABLE 4 Results of removal of benzylamine in the presence ofN-benzylmethylamine Ratio (BnNH₂/BnNHMe, Time %) Content of BnNH₂ (%)Content of BnNHMe (%) (hour) A B C A B C A B C 0 23.5 23.5 21.8 100 100100 100 100 100 1 15.2 21.6 19.4 53.5 93.7 89.2 82.9 100 100 2 10.4 20.117.8 39.2 86.0 83.4 88.4 100 100 4 5.87 17.5 15.2 20.4 71.6 72.8 81.595.0 99.8 6 3.98 16.6 13.9 13.9 53.2 61.7 81.9 81.8 99.4 7 3.0 14.1 13.49.99 48.3 56.7 78.1 80.8 92.4 9 2.9 12.7 11.8 9.43 48.6 52.7 76.3 90.196.9

[0088] TABLE 5 Results of removal of benzylamine in the presence ofN-benzylmethylamine Time Ratio (BnNH₂/BnNHMe, %) (hour) D E F G H 0 37.035.2 29.5 32.6 29.2 1 31.8 14.2 18.2 22.7 17.6 2 28.4 9.67 14.5 16.113.6 3 21.5 6.07 12.9 13.2 11.3 4 6.04 5 16.3 9.03 9.02 8.36 6 14.7 3.787.37 7.74 6.85 7 13.6 2.67 6.54 6.36 6.08 8 12.3 1.53 5.60 4.56 9 11.32.21 5.04 2.78 4.36 10 11.0 1.28 4.10 11 10.3 0.83 2.67 3.03 24 6.811.45 0.49 0.81 2.42 30 5.0 0.94 0.48 0 1.62

[0089] Table 6 shows the effect of solvent on the removal of benzylaminein a mixture of N-benzylmethylamine and benzylamine. Benzylamine isselectively removed in all the solvents systems. 2-Propanol gave muchbetter results than methanol while a mixture of 2-propanol andtetrahydrofuran or dichloromethane (DCM) gave slightly better puritiesand recoveries for the secondary amine, N-benzylmethylamine. TABLE 6^(a).Effects of Solvents on Removal of BnNH2 in a Mixture ofBnNHMe/BnNH2 Solvents Purity (%, HPLC)^(b) Recovery of BnNHMe (%) MeOH93 41 MeOH/DCM(1:1) 95 71 2-PrOH 96 72 2-PrOH/DCM (1:1) 100 652-PrOH/THF (1:1) 100 69

Example 5 Use of Scavenger Resin to Remove Excess Primary Amine in aReductive Alkylation r Action

[0090] Several secondary amines were individually prepared by reductivealkylation as shown in Scheme 1.

[0091] In each reaction, benzaldehyde was reacted with a primary amineselected from benzylamine, 2-furylmethylamine, 2-phenylethylamine,1-naphthylmethylamine, 2,2-diphenylethylamine, and diphenylmethylamineto give the corresponding imine. Propan-2-ol or methanol were used assolvents for this reaction. The reduction of the imines (3) to give thecorresponding secondary amines was solvent dependent, methanol provingto be much more rapid than in propan-2-ol. The reaction of the resultingprimary and secondary amine mixture with the Scavenger Resin prepared inExample 1 was then either carried out in propan-2-ol/tetrahydrofuran orin methanol/dichloromethane. The results obtained are given in Table 7.TABLE 7 Results on Reductive Alkylation Solvents Purity Yield R1 stepa + b step c^(a) Compound (%) (%) Phenyl 2-PrOH 2-PrOH/THF 3 100^(b) 602-Furyl 2-PrOH 2-PrOH/THF 3 100^(b) 68 Benzyl 2-PrOH 2-PrOH/THF 3100^(b) 70 Diphenyl 2-PrOH 2-PrOH/THF 3  97^(b) 63 1-Naphthyl 2-PrOH2-PrOH/THF 3 100^(b) 56 Benzhydryl 2-PrOH 2-PrOH/THF 3  98^(b) 54 PhenylMeOH MeOH/DCM 4 100^(c) 81 2-Furyl MeOH MeOH/DCM 4 100^(b) 88 BenzylMeOH MeOH/DCM 4 100^(c) 87 Diphenyl MeOH MeOH/DCM 4  87^(b) 801-Naphthyl MeOH MeOH/DCM 4 100^(b) 72 Benzhydryl MeOH MeOH/DCM 4  93^(b)69

Example 6 Removal of an Elecrophile from Solution by the Scavenger Resin

[0092] The scavenger resin prepared in Example 2 was tested as ascavenger for aromatic aldehydes. The basis of the test is theKnoevenagel condensation, reaction of an active methylene compound withan aldehyde in the presence of a base and is outlined in the schemebelow:

[0093] To a solution of benzaldehyde (0.5 mmol) and base (see Table 8)in solvent (8.0 ml) was added scavenger resin (1.0 g, 3.0 mmol) preparedaccording to Example 2. Aliquots of the solution (10 μl) were taken fromthe suspension at time intervals and diluted with acetonitrile (to 1.0ml). The samples were analysed by HPLC to determine the extent ofremoval of the benzaldehyde as a function of time. HPLC conditions usedwere: Gradient from water (0.1% TFA) to MeCN (0.042% TFA) over 20minutes. Benzaldehyde (tR 12.3 min.).

[0094] The results are shown in Table 9. TABLE 8 Solvents and Baseemployed in Experiments to sh w the removal of benzaldehyde withscavenger resin Experiment Solvent Base* A dichloromethane 2.4 eq.piperidine acetate B trimethyl orthoformate 1 eq. piperidine acetate

[0095] TABLE 9 Results showing removal of benzaldehyde with scavengerresin Percentage Time Benzaldehyde (%) (h) A B 0 100 100 1 31.4 25.7 323.5 10.2 5 24.1 6.6 7 27.8 5.8 9 28.1 5.3 24 31.9 5.4 48 18.4 4.3

1. A process for removing primary amines from solution wherein asolution comprising a primary amine is contacted with a scavenger resin,whereby the scavenger resin binds to at least some of the primary aminein solution thereby decreasing the amount of primary amine in solution,characterised in that the scavenger resin comprises pendant groupsselected from 1,3-ketoesters or 1,3-ketoamides or mixtures thereofattached to a polymer support.
 2. A process for removing ofelectrophiles from solution wherein a solution comprising anelectrophile is contacted with a scavenger resin, whereby the scavengerresin binds to at least a some of the electrophile in solution therebydecreasing levels of electrophile in solution characterised in that thescavenger resin comprises pendant groups selected from 1,3-ketoesters or1,3-ketoamides or mixtures thereof attached to a polymer support.
 3. Ascavenger resin obtainable by the polymerisation of a compositioncomprising one or more monomers containing only one polymerisable doublebond, one or more monomers containing two or more polymerisable doublebonds, and a functionalised monomer comprising pendant 1,3-ketoester or1,3-ketoamide groups attached by means of a linker to a single monomertype.
 4. A crosslinked polymer bead scavenger resin obtainable byaqueous suspension polymerisation of a composition comprising one ormore monomers containing only one polymerisable double bond, one or moremonomers containing two or more polymerisable double bonds, and afunctionalised monomer comprising pendant 1,3-ketoester or 1,3-ketoamidegroups attached by means of a linker to a single monomer type.
 5. Ascavenger resin according to either of claim 3 or claim 4 wherein a) themonomer(s) containing only one polymerisable double bond is selectedfrom the group consisting of styrene and substituted styrenes; alkylesters of mono-olefinically unsaturated dicarboxylic acids; vinyl estersof carboxylic acids and vinyl esters of versatic acid; acrylamides;methacrylamides; nitrile monomers; and esters of acrylic and methacrylicacid; and b) the monomer(s) containing two or more polymerisable doublebonds is selected from the group consisting of divinylbenzene,trivinylbenzene, and multifunctional acrylates and methacrylates.
 6. Ascavenger resin according to claim 5 wherein a) the monomer(s)containing only one polymerisable double bond is selected from the groupconsisting of styrene, α-methyl styrene, methyl styrene, t-butylstyrene, bromo styrene, acetoxy styrene, di-n-butyl maleate, di-n-butylfumarate, vinyl acetate, vinyl propionate, vinyl laurate, vinyl estersof versatic acid, methyl acrylamide, ethyl acrylamide, methylmethacrylamide, ethyl methacrylamide, acrylonitrile, methacrylonitrile,methyl acrylate, ethyl acrylate, n-butyl acrylate, 2-ethylhexylacrylate, i-propyl acrylate, n-propyl acrylate, methyl methacrylate,ethyl methacrylate, n-butyl methacrylate, 2-ethylhexyl methacrylate,i-propyl methacrylate, n-propyl acrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, N,N-dimethylaminoethyl acrylate, andN,N-dimethylaminoethyl methacrylate; and b) the monomer(s) containingtwo or more polymerisable double bonds is selected from the groupconsisting of divinylbenzene, trivinylbenzene, ethylene glycoldiacrylate, ethylene glycol dimethacrylate, trimethylolpropanetriacrylate, trimethylolpropane trimethacrylate, ethylene bisacrylamide,pentaerythritol triacrylate, pentaerythritol tetraacrylate,pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate andN,N-bis-acryloyl ethylene diamine.
 7. A scavenger resin according to anyone of claims 3 to 6 wherein the functionalised monomer comprisingpendant 1,3-ketoester or 1,3-ketoamide groups attached by means of alinker to a single monomer type has the general formula 2:

wherein R¹ is an optionally substituted hydrocarbyl, perhalogenatedhydrocarbyl or heterocyclyl group; X is O or NR², wherein the freevalence of O or NR² is bonded to a polymer support optionally via alinker; R² is hydrogen, an optionally substituted hydrocarbyl, orheterocyclyl group; R³ is an optionally substituted hydrocarbyl,perhalogenated hydrocarbyl or heterocyclyl group; and L is a linkinggroup.
 8. A scavenger resin according to claim 7 wherein L is selectedfrom the group consisting of optionally substituted methylene,polymethylene, ether, polyether or cyclic bridging units.
 9. A scavengerresin according to claim 8 wherein L is selected from the groupconsisting of optionally substituted linear and branched alkylene chainscomprising up to 20 carbon atoms; optionally substituted linear andbranched alkylene-oxy-alkylene chains or poly(alkyleneoxy)-alkylenechains comprising up to 150 carbon atoms and up to 40 oxygen atoms; andoptionally substituted aromatic, saturated and partially unsaturatedring systems comprising from 3 to 10 carbon atoms in the largest ring.10. A scavenger resin according to claim 9 wherein L is selected fromthe group consisting of —CH₂—, —CH₂CH₂—, —(CH₂)₃—, —CH₂CH(CH₃)—,—CH₂C(CH₃)₂—, —CH₂—O—CH₂—, —CH₂CH₂—O—CH₂CH₂—, —(CH₂)₃—O—(CH₂)₃—,—CH₂CH(CH₃)—O—CH₂CH₂—, —CH₂CH(CH₃)—O—CH₂CH(CH₃)— chains,—[CH₂CH₂—O]_(n)—CH₂CH₂— and —[CH₂CH(CH₃)—O]_(n)—CH₂CH(CH₃)— chains wheren=2, 3 or 4, —CH₂C₆H₄CH₂— and —CH₂C₆H₁₀CH₂.
 11. A scavenger resinaccording to any one of claim 7 to 10 wherein the functionalised monomercomprising pendant 1,3-ketoester or 1,3-ketoamide groups attached bymeans of a linker to a single monomer type is selected from the groupconsisting of the following


12. A scavenger resin according to any one of claims 7 to 10 wherein thefunctionalised monomer comprising pendant 1,3-ketoester or 1,3-ketoamidegroups attached by means of a linker to a single monomer type isacetoacetoxyethyl methacrylate.
 13. A scavenger resin according to claim3 or claim 4 wherein the composition comprises one or more monomersselected from the group consisting of acetoacetoxyethyl acrylate,acetoacetoxyethyl methacrylate, acetoacetoxypropyl acrylate, andacetoacetoxypropyl methacrylate, one or more monomers selected from thegroup consisting of styrene, methyl acrylate, ethyl acrylate, methylmethacrylate, ethyl acrylate, and one or more monomers selected from thegroup consisting of divinylbenzene, trivinylbenzene ethylene glycoldiacrylate, ethylene glycol dimethacrylate, trimethylolpropanetriacrylate, trimethylolpropane trimethacrylate, ethylene bisacrylamide,pentaerythritol triacrylate, pentaerythritol tetraacrylate,pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate andN,N-bis-acryloyl ethylene diamine.
 14. A scavenger resins according toclaim 13 wherein the composition comprises acetoacetoxyethylmethacrylate, styrene and divinylbenzene.
 15. A process according toeither of claim 1 or claim 2 wherein the scavenger resin is a scavengerresin according to any one of claims 3 to 14.